EP1487475A1 - Use of enzyme inhibitors with aminopeptidase n and/or dipeptidylpeptidase iv activities and pharmaceutical preparations produced therefrom for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states - Google Patents

Use of enzyme inhibitors with aminopeptidase n and/or dipeptidylpeptidase iv activities and pharmaceutical preparations produced therefrom for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states

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EP1487475A1
EP1487475A1 EP03709761A EP03709761A EP1487475A1 EP 1487475 A1 EP1487475 A1 EP 1487475A1 EP 03709761 A EP03709761 A EP 03709761A EP 03709761 A EP03709761 A EP 03709761A EP 1487475 A1 EP1487475 A1 EP 1487475A1
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xaa
inhibitors
derivatives
apn
amino acid
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French (fr)
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EP1487475B1 (en
Inventor
Siegfried Ansorge
Harald Gollnick
Klaus Martin-Luther-Universität NEUBERT
Christos C. Zouboulis
Jürgen Martin-Luther-Universität FAUST
Uwe Universität Magdeburg Inst. LENDECKEL
Dirk Uni. Magdeburg Inst. Immunologie REINHOLD
Robert Vetter
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IMTM GmbH
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IMTM GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention describes the inhibition of the DNA synthesis of sebocytes required for proliferation by the action of inhibitors of aminopeptidase N (APN, EC3.4.11.2, CD13) or / and dipeptidyl peptidase IV (DP IV, EC 3.4.14.5, CD26 ) as a result of the individual, simultaneous or immediately successive application of specific inhibitors of these enzymes or enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) on the basis of amino acid derivatives, peptides or peptide derivatives, by which the proliferation (DNA synthesis) is suppressed by sebocytes.
  • APN aminopeptidase N
  • DP IV dipeptidyl peptidase IV
  • a number of dermatological diseases are associated with sebocytic hyperproliferation and changed differentiation states. These include both benign follicular hyperproliferative conditions (acne, acneiform follicular reactions, steatocystoma multiplex, sebaceous gland nevi, senile sebaceous gland hypertrophy, seborrhea of the skin and hair) and malignant follicular hyperproliferative conditions (mixed tumors, sebaceous glands, sebaceous tumors, talc tumors CA).
  • benign follicular hyperproliferative conditions acne, acneiform follicular reactions, steatocystoma multiplex, sebaceous gland nevi, senile sebaceous gland hypertrophy, seborrhea of the skin and hair
  • malignant follicular hyperproliferative conditions mixed tumors, sebaceous glands, sebaceous tumors, talc tumors CA.
  • Peptidases such as dipeptidyl petidase IV and aminopeptidase N or enzymes with a similar effect are particularly interesting for the regulation or modulation of interactions between cells, since they are localized, among other things, as ectoenzymes in the plasma membrane of the cells, enter into interactions with other extracellular structures, through peptidergic messenger substances Activate or inactivate enzyme-catalyzed hydrolysis and are therefore important for cell-cell Communication is [Yaron A, et al .: Proline-dependent structural and biological properties of peptides and proteins. Crit Rev Biochem Mol Biol 1993; 28: 31-81; Vanhoof G, et al .: Proline motifs in peptides and their biological processing. FASEB J 1995; 9: 736-744].
  • membrane-active peptides such as DP IV or APN play a key role in the process of activation and clonal expansion of immune cells, in particular T-lymphocytes
  • T-lymphocytes T-lymphocytes
  • Fleischer B CD26 a surface protease involved in T-cell activation. Immunology Today 1994; 15: 180-184; Lendeckel U et al .: Role of alanyl aminopeptidase in growth and function of human T cells. International Journal of Molecular Medicine 1999; 4: 17-27; Riemann D et al .: CD13 - not just a marker in leukemia typing. Immunology Today 1999; 20: 83-88].
  • mitogen-stimulated mononuclear cells or enriched T-lymphocytes
  • DNA synthesis production and secretion of immunostimulating cytokines (IL-2, IL-6, IL-12, IFN- ⁇ ) and helper functions for B cells ( IgG and IgM synthesis)
  • cytokines IL-2, IL-6, IL-12, IFN- ⁇
  • helper functions for B cells IgG and IgM synthesis
  • Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro.
  • the invention is based on the surprising finding that the individual or simultaneous effect of inhibitors of the dipeptidyl peptidase IV / CD26 and aminopeptidase N / CD13 expressed on or in sebocytes or enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) are: Inhibits proliferation (DNA synthesis) of these cells.
  • our invention shows that for the treatment and prevention of dermatological diseases with sebaceous hyperproliferation and changed differentiation states (benign follicular hyperproliferation conditions like acne, acneiform follicular reactions steatocystoma multiplex, sebaceous nevi, senile Talgdrüsenhypertrophie, seborrhea of the skin and hair and malignant follicular hyperproliferation conditions such as mixed tumors, sebaceomas, sebaceous gland tumors, sebaceous gland CA), for whose development the proliferation of sebocytes is of central importance, the single or simultaneous application of inhibitors of DP IV and APN or enzymes of the same substrate specificity (APN or / and DP IV-analogous enzyme activity) or corresponding preparations and dosage forms thereof are suitable.
  • benign follicular hyperproliferation conditions like acne, acneiform follicular reactions steatocystoma multiplex, sebaceous nevi, senile
  • the invention is based on the findings that the DNA synthesis of sebocytes is significantly inhibited by the administration of inhibitors of dipeptidyl peptidase IV or / and aminopeptidase N.
  • DP IV or / and APN inhibitors would represent a completely new, probably very effective, possibly inexpensive form of therapy for the diseases mentioned and a valuable alternative component of the existing therapy concepts.
  • inhibitors of dipeptidyl peptidase IV or / and of aminopeptidase N or enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) applied according to the invention can be used in pharmaceutically acceptable formulation complexes as inhibitors, substrates, pseudo-substrates, inhibitory peptides and peptide derivatives and as Antibodies to these enzymes are used.
  • Preferred inhibitors for alanyl aminopeptidase are Bestaun (Ubenimex), Actinonin, Probestin, Phebestin, RB3014 or Leuhistin.
  • the inhibitors are administered simultaneously with known carriers.
  • the administration takes place on the one hand as a topical application in the form of e.g. Creams, ointments, pastes, gels, solutions, sprays, liposomes and nanosomes,
  • the human sebocyte cell line SZ95 which is accepted as a cell model for acne, strongly expresses DP IV and APN (Fig. 1).
  • the mRNA of APN and DP IV can be detected on these cells (Fig. 2).
  • Fig. 1 Flow cytometric detection of the expression of DP IV (CD26) and APN (CD13) on SZ95 cells
  • Fig. 2 Detection of the mRNA expression of DP IV (CD26) and APN (CD13) on SZ95 lines using RT-PCR
  • Fig. 3 Dose-dependent effect of DP IV (Lys [Z (NO 2 )] thiazolidide) and aminopeptidase N (actinonin) inhibitors on the DNA synthesis of human SZ95 sebocytes.
  • the cells were incubated for 48 hours with the indicated concentrations of the inhibitors. Then 3 [H] methyl thymidine was added to the culture medium and after a further 6 hours the amount of 3 [H] thymidine incorporated into the DNA was measured.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a process for the-inhibition of the DNA synthesis necessary for the proliferation of human sebaceous cells (sebocytes) by the isolated or joint effect of inhibitors of alanyl aminopeptidase (APN) and dipetidyl peptidase IV (DP IV) expressed by these cells. The DNA synthesis (proliferation) of human sebaceous cells is inhibited by the administration of the inhibitors of APN and/or of DP IV depending on the dose. Our invention shows that, for a therapy and for a prevention of dermatological diseases with sebaceous hyperproliferation and modified conditions of differentiation, the application of inhibitors of the above-mentioned enzymes and of corresponding pharmaceutical preparations and dosage forms thereof is suitable.

Description

Verwendung der Inhibitoren von Enzymen mit Aktivitäten der Use of the inhibitors of enzymes with activities of
Aminopeptidase N und/oder der Dipeptidylpeptidase IV und pharmazeutischen Zubereitungen daraus zur Therapie und Prävention dermatologischer Erkrankungen mit sebozytärer Hyperproliferation und veränderten DifferenzierungszuständenAminopeptidase N and / or dipeptidyl peptidase IV and pharmaceutical preparations therefrom for the therapy and prevention of dermatological diseases with sebocytic hyperproliferation and changed differentiation states
Die Erfindung beschreibt die Hemmung der für die Proliferation notwendigen DNA-Synthese von Sebozyten durch die Wirkung von Inhibitoren der Aminopeptidase N (APN, EC3.4.11.2, CD13) oder/und der Dipeptidylpeptidase IV (DP IV, EC 3.4.14.5, CD26) im Ergebnis der einzelnen, simultanen oder zeitlich unmittelbar aufeinanderfolgenden Applikation von jeweils spezifischen Inhibitoren dieser Enzyme oder Enzymen gleicher Substratspezifität (APN- oder/und DP IV-analoge Enzymaktivität) auf der Basis von Aminosäurederivaten, Peptiden oder Peptidde- rivaten, durch welche die Proliferation (DNA-Synthese) von Sebozyten suppri- miert wird.The invention describes the inhibition of the DNA synthesis of sebocytes required for proliferation by the action of inhibitors of aminopeptidase N (APN, EC3.4.11.2, CD13) or / and dipeptidyl peptidase IV (DP IV, EC 3.4.14.5, CD26 ) as a result of the individual, simultaneous or immediately successive application of specific inhibitors of these enzymes or enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) on the basis of amino acid derivatives, peptides or peptide derivatives, by which the proliferation (DNA synthesis) is suppressed by sebocytes.
Eine Reihe dermatologischer Erkrankungen gehen mit sebozytärer Hyperproliferation und veränderten Differenzierungszuständen einher. Zu ihnen gehören sowohl benigne follikuläre Hyperproliferationszustände (Akne, akneiforme folliku- läre Reaktionen, Steatocystoma multiplex, Talgdrüsen-Naevi, senile Talgdrüsenhypertrophie, Seborrhoe der Haut und Haare) als auch maligne follikuläre Hyperproliferationszustände (Mischtumoren, Sebaceome, Talgdrüsen-Tumoren, Talg- drüsen-CA).A number of dermatological diseases are associated with sebocytic hyperproliferation and changed differentiation states. These include both benign follicular hyperproliferative conditions (acne, acneiform follicular reactions, steatocystoma multiplex, sebaceous gland nevi, senile sebaceous gland hypertrophy, seborrhea of the skin and hair) and malignant follicular hyperproliferative conditions (mixed tumors, sebaceous glands, sebaceous tumors, talc tumors CA).
Peptidasen wie die Dipeptidylpetidase IV und die Aminopeptidase N oder ähnlich wirkende Enzyme sind für die Regulation bzw. Modulation von Wechselwirkungen zwischen Zellen besonders interessant, da sie u. a. als Ektoenzyme in der Plasmamembran der Zellen lokalisiert sind, Interaktionen mit anderen extrazellulären Strukturen eingehen, peptiderge Botenstoffe durch enzymkatalysierte Hydrolyse aktivieren bzw. inaktivieren und dadurch wichtig für die Zeil-Zeil- Kommunikation sind [Yaron A, et al.: Proline-dependent structural and biological properties of peptides and proteins. Crit Rev Biochem Mol Biol 1993;28:31-81 ; Vanhoof G, et al.: Proline motifs in peptides and their biological processing. FASEB J 1995;9:736-744].Peptidases such as dipeptidyl petidase IV and aminopeptidase N or enzymes with a similar effect are particularly interesting for the regulation or modulation of interactions between cells, since they are localized, among other things, as ectoenzymes in the plasma membrane of the cells, enter into interactions with other extracellular structures, through peptidergic messenger substances Activate or inactivate enzyme-catalyzed hydrolysis and are therefore important for cell-cell Communication is [Yaron A, et al .: Proline-dependent structural and biological properties of peptides and proteins. Crit Rev Biochem Mol Biol 1993; 28: 31-81; Vanhoof G, et al .: Proline motifs in peptides and their biological processing. FASEB J 1995; 9: 736-744].
Es ist gezeigt worden, dass im Prozess der Aktivierung und klonalen Expansion von Immunzellen, insbesondere von T-Lymphozyten, membranständige Peptida- sen wie DP IV oder APN eine Schlüsselrolle spielen [Fleischer B: CD26 a surface protease involved in T-cell activation. Immunology Today 1994; 15:180-184; Lendeckel U et al.: Role of alanyl aminopeptidase in growth and function of human T cells. International Journal of Molecular Medicine 1999; 4:17-27; Riemann D et al.: CD13 - not just a marker in leukemia typing. Immunology Today 1999; 20:83-88]. Verschiedene Funktionen Mitogen-stimulierter mononukleärer Zellen (MNZ) oder angereicherter T-Lymphozyten wie DNA-Synthese, Produktion und Sekretion von immunstimulierenden Zytokinen (IL-2, IL-6, IL-12, IFN-γ) und Helferfunktionen für B-Zellen (lgG- und IgM-Synthese) können in Gegenwart von spezifischen Inhibitoren der DP IV oder der APN gehemmt werden [Schön E et al.: The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes. Biomed. Biochim. Acta 1985; 2: K9-K15; Schön E et al.: The role of dipeptidyl peptidase IV in human T lymphocyte activation. Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro. Eur. J. Immunol. 1987; 17: 1821-1826; Reinhold D et al.: Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor ß1 in PWM-stimulated PBMNC and T cells. Immunology 1997; 91 : 354-360; Lendeckel U et al.: Induction of the membrane alanyl aminopeptidase gene and surface expression in human T-cells by mitogenic activation. Biochem. J. 1996; 319: 817-823; Kähne T et al.: Dipeptidyl peptidase IV: A cell surface peptidase involved in regulating T cell growth (Review). Int. J. Mol. Med. 1999; 4: 3-15; Lendeckel U et al.: Role of alanyl aminopeptidase in growth and function of human T cells (Review). Int. J. Mol. Med. 1999; 4: 17-27]. Es ist bereits bekannt, daß die Behandlung von Autoimmunerkrankungen und Transplantatabstoßung durch Hemmung der auf Immunzellen lokalisierten Dipeptidylpetidase IV mit Hilfe von synthetischen Inhibitoren möglich ist (z. B. EP764151 A1 , WO09529691 , EP731789 A1, EP528858).It has been shown that membrane-active peptides such as DP IV or APN play a key role in the process of activation and clonal expansion of immune cells, in particular T-lymphocytes [Fleischer B: CD26 a surface protease involved in T-cell activation. Immunology Today 1994; 15: 180-184; Lendeckel U et al .: Role of alanyl aminopeptidase in growth and function of human T cells. International Journal of Molecular Medicine 1999; 4: 17-27; Riemann D et al .: CD13 - not just a marker in leukemia typing. Immunology Today 1999; 20: 83-88]. Various functions of mitogen-stimulated mononuclear cells (MNZ) or enriched T-lymphocytes such as DNA synthesis, production and secretion of immunostimulating cytokines (IL-2, IL-6, IL-12, IFN-γ) and helper functions for B cells ( IgG and IgM synthesis) can be inhibited in the presence of specific inhibitors of DP IV or APN [Schön E et al .: The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes. Biomed. Biochim. Acta 1985; 2: K9-K15; Schön E et al .: The role of dipeptidyl peptidase IV in human T lymphocyte activation. Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro. Eur. J. Immunol. , 1987; 17: 1821-1826; Reinhold D et al .: Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor ß1 in PWM-stimulated PBMNC and T cells. Immunology 1997; 91: 354-360; Lendeckel U et al .: Induction of the membrane alanyl aminopeptidase gene and surface expression in human T-cells by mitogenic activation. Biochem. J. 1996; 319: 817-823; Kähne T et al .: Dipeptidyl peptidase IV: A cell surface peptidase involved in regulating T cell growth (review). Int. J. Mol. Med. 1999; 4: 3-15; Lendeckel U et al .: Role of alanyl aminopeptidase in growth and function of human T cells (review). Int. J. Mol. Med. 1999; 4: 17-27]. It is already known to treat autoimmune diseases and graft rejection by inhibiting the dipeptidyl petidase IV located on immune cells with the aid of synthetic inhibitors (e.g. EP764151 A1, WO09529691, EP731789 A1, EP528858).
Der Erfindung liegt der überraschende Befund zugrunde, dass die einzelne oder gleichzeitige Wirkung von Inhibitoren der auf bzw. in Sebozyten exprimierten Dipeptidylpeptidase IV/CD26 und Aminopeptidase N/CD13 oder Enzyme gleicher Substratspezifität (APN- oder/und DP IV-analoge Enzymaktivität), die Proliferation (DNA-Synthese) dieser Zellen hemmt.The invention is based on the surprising finding that the individual or simultaneous effect of inhibitors of the dipeptidyl peptidase IV / CD26 and aminopeptidase N / CD13 expressed on or in sebocytes or enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) are: Inhibits proliferation (DNA synthesis) of these cells.
Unsere Erfindung zeigt, dass zur Therapie und zur Prävention von dermatologischen Erkrankungen mit sebozytärer Hyperproliferation und veränderten Differenzierungszuständen (benigne follikuläre Hyperproliferationszustände wie Akne, akneiforme follikuläre Reaktionen, Steatocystoma multiplex, Talgdrüsen-Naevi, senile Talgdrüsenhypertrophie, Seborrhoe der Haut und Haare als auch maligne follikuläre Hyperproliferationszustände wie Mischtumoren, Sebaceome, Talgdrüsen-Tumoren, Talgdrüsen-CA), für deren Entstehung die Proliferation von Sebozyten eine zentrale Bedeutung hat, die einzelne oder gleichzeitige Applikation von Hemmstoffen der DP IV und der APN oder Enzymen gleicher Substratspezifität (APN- oder/und DP IV-analoge Enzymaktivität) bzw. entsprechender Zubereitungen und Darreichungsformen daraus geeignet sind.Our invention shows that for the treatment and prevention of dermatological diseases with sebaceous hyperproliferation and changed differentiation states (benign follicular hyperproliferation conditions like acne, acneiform follicular reactions steatocystoma multiplex, sebaceous nevi, senile Talgdrüsenhypertrophie, seborrhea of the skin and hair and malignant follicular hyperproliferation conditions such as mixed tumors, sebaceomas, sebaceous gland tumors, sebaceous gland CA), for whose development the proliferation of sebocytes is of central importance, the single or simultaneous application of inhibitors of DP IV and APN or enzymes of the same substrate specificity (APN or / and DP IV-analogous enzyme activity) or corresponding preparations and dosage forms thereof are suitable.
Im einzelnen liegen der Erfindung die Befunde zugrunde, dass die DNA-Synthese von Sebozyten durch die Gabe von Inhibitoren der Dipeptidylpeptidase IV oder/und der Aminopeptidase N signifikant inhibiert wird.In particular, the invention is based on the findings that the DNA synthesis of sebocytes is significantly inhibited by the administration of inhibitors of dipeptidyl peptidase IV or / and aminopeptidase N.
Die oben genannten Erkrankungen werden bisher topisch und/oder systemisch mit Antibiotika und/oder antiproliferativen und differenzierenden Substanzen (Antiandrogenen, 13-cis-Retinsäure u. a) behandelt. Insbesondere bei der systemischen Anwendung treten häufig unerwünschte Nebenwirkungen auf. DiesThe above-mentioned diseases have hitherto been treated topically and / or systemically with antibiotics and / or antiproliferative and differentiating substances (antiandrogens, 13-cis-retinoic acid, etc.). In systemic use in particular, undesirable side effects often occur. This
sind u. a. Teratogenität, Lipidstoffwechselstörungen, psychoreaktive Erscheinungen, gastrointestinale Beschwerden sowie muco-cutane irritative Reaktionen. Der Einsatz von DP IV- oder/und APN-Inhibitoren würde bei den genannten Erkrankungen eine gänzlich neuartige, vorraussichtlich sehr effektive, möglicherweise kostengünstige Therapieform und einen wertvollen alternativen Bestandteil der bestehenden Therapiekonzepte darstellen.These include teratogenicity, lipid metabolism disorders, psychoreactive symptoms, gastrointestinal complaints and mucocutaneous irritative reactions. The use of DP IV or / and APN inhibitors would represent a completely new, probably very effective, possibly inexpensive form of therapy for the diseases mentioned and a valuable alternative component of the existing therapy concepts.
Die erfindungsgemäß applizierten Inhibitoren der Dipeptidylpeptidase IV oder/und der Aminopeptidase N oder Enzymen gleicher Substratspezifität (APN- oder/und DP IV-analoge Enzymaktivität) können in pharmazeutisch anwendbaren Formulierungs-komplexen als Inhibitoren, Substrate, Pseudosubstrate, inhibitorisch wirkende Peptide und Peptidderivate sowie als Antikörper dieser Enzyme zur Anwendung kommen.The inhibitors of dipeptidyl peptidase IV or / and of aminopeptidase N or enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) applied according to the invention can be used in pharmaceutically acceptable formulation complexes as inhibitors, substrates, pseudo-substrates, inhibitory peptides and peptide derivatives and as Antibodies to these enzymes are used.
Bevorzugte Effektoren sind beispielsweise für die DP IV Xaa-Pro-Dipeptide, entsprechende Derivate, vorzugsweise Dipeptidphosphonsäure-diarylester und deren Salze, Xaa-Xaa-(Trp)-Pro-(Xaa)n-Peptide (n=0-10), entsprechende Derivate und deren Salze bzw. Aminosäure (Xaa)-amide, entsprechende Derivate und deren Salze, wobei Xaa eine α-Aminosäure/lminosäure bzw. ein - Aminosäurederivat Iminosäurederivat, vorzugsweise Nε-4-Nitrobenzyl-oxycarbon- yl-L-Lysin, L-Prolin, L-Tryptophan,L-lsoleucin, L-Valin ist und als Amidstruktur cyclische Amine, z.B. Pyrrolidin, Piperidin, Thiazolidin und deren Derivate. Derartige Verbindungen und deren Herstellung wurden in einem früheren Patent beschrieben (K. Neubert et al. DD296075A5). Bevorzugte Inhibitoren für die Alanyl- Aminopeptidase sind Bestaun (Ubenimex), Actinonin, Probestin, Phebestin, RB3014 oder Leuhistin.Preferred effectors are, for example for the DP IV Xaa-Pro dipeptides, corresponding derivatives, preferably dipeptidephosphonic acid diaryl esters and their salts, Xaa-Xaa- (Trp) -Pro- (Xaa) n-peptides (n = 0-10) Derivatives and their salts or amino acid (Xaa) amides, corresponding derivatives and their salts, where Xaa is an α-amino acid / amino acid or an amino acid derivative, amino acid derivative, preferably N ε -4-nitrobenzyloxycarbonyl-L-lysine, L-proline, L-tryptophan, L-isoleucine, L-valine and cyclic amines as the amide structure, for example pyrrolidine, piperidine, thiazolidine and their derivatives. Such compounds and their preparation have been described in a previous patent (K. Neubert et al. DD296075A5). Preferred inhibitors for alanyl aminopeptidase are Bestaun (Ubenimex), Actinonin, Probestin, Phebestin, RB3014 or Leuhistin.
Die Inhibitoren werden simultan mit bekannten Trägerstoffen verabreicht. Die Verabreichung erfolgt einerseits als topische Applikation in Form von z.B. Cremes, Salben, Pasten, Gelen, Lösungen, Sprays, Lipo- und Nanosomen,The inhibitors are administered simultaneously with known carriers. The administration takes place on the one hand as a topical application in the form of e.g. Creams, ointments, pastes, gels, solutions, sprays, liposomes and nanosomes,
Schüttelmixturen, Hydrokolloidverbänden, Pflaster und ähnliche neue Trägersubstrate, Jet-Injektion bzw. anderen dermatologischen GrundlagenΛ/ehikeln einschließlich instillativer Applikation und andererseits als systemische Applikation zur oralen, transdermalen, intravenösen, subcutanen, intracutanen, intramuskulären Anwendung in geeigneten Rezepturen bzw. in geeigneter Galenik.Shake mixtures, hydrocolloid dressings, plasters and similar new carrier substrates, jet injection or other dermatological basics / articles including instillative application and on the other hand as systemic application for oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular use in suitable formulations or in suitable galenics.
Ausführungsbeispiel 1Embodiment 1
Inhibierung der DNA-Synthese der immortalisierten humanen Sebozyten- zelllinie SZ95 durch Inkubation mit synthetischen Inhibitoren der DP IV oder/und der APNInhibition of the DNA synthesis of the immortalized human sebocyte cell line SZ95 by incubation with synthetic inhibitors of the DP IV or / and the APN
Unsere Untersuchungen zeigen, dass die DNA-Synthese der immortalisierten humanen Sebozytenzelllinie SZ95 (Zouboulis C.C. et al: Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J. Invest. Dermatol. 1999, 113: 1011-1020) durch die Administration von Inhibitoren der DP IV (Lys[Z(NO2)]-thiazolidid) oder/und der APN (Actinonin) dosisabhängig gehemmt wird.Our investigations show that the DNA synthesis of the immortalized human sebocyte cell line SZ95 (Zouboulis CC et al: Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95) by J. Invest. Dermatol. 1999, 113: 1011-1020) the administration of inhibitors of DP IV (Lys [Z (NO 2 )] - thiazolidide) and / or APN (actinonin) is inhibited in a dose-dependent manner.
Die humane Sebozytenzelllinie SZ95, welche als Zellmodell für die Akne akzeptiert ist, exprimiert stark DP IV und APN (Abb. 1). Die Enzymaktivität der DP IV von vitalen Zellen beträgt 38 + 18 pkat/106 Zellen, die der APN beträgt 262 + 58 pkat/106 Zellen (n = 3). Entsprechen ist die mRNA von APN und DP IV auf diesen Zellen nachweisbar (Abb. 2). The human sebocyte cell line SZ95, which is accepted as a cell model for acne, strongly expresses DP IV and APN (Fig. 1). The enzyme activity of the DP IV of vital cells is 38 + 18 pkat / 10 6 cells, that of the APN is 262 + 58 pkat / 10 6 cells (n = 3). Correspondingly, the mRNA of APN and DP IV can be detected on these cells (Fig. 2).
Abb. 1 : Durchflußzytometrischer Nachweis der Expression von DP IV (CD26) und APN (CD13) auf SZ95-ZellenFig. 1: Flow cytometric detection of the expression of DP IV (CD26) and APN (CD13) on SZ95 cells
SZ95-Zellen wurden 48 h mit den oben genannten Inhibitoren inkubiert und anschließend über die Messung der 3[Hj-Thymidin-lnkorporation die DNA- Synthese bestimmt, wie bei Reinhoid et al. beschrieben (Reinhoid D et al.: Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor ß1 in PWM-stimulated PBMNC and T cells. Immunology 1997; 91: 354-360). Abbildung 2 zeigt die dosisab-hängige Hemmung der DNA-Synthese.SZ95 cells were incubated for 48 hours with the inhibitors mentioned above and the DNA synthesis was then determined by measuring the 3 [Hj-thymidine incorporation, as described by Reinhoid et al. (Reinhoid D et al .: Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells. Immunology 1997; 91: 354-360). Figure 2 shows the dose-dependent inhibition of DNA synthesis.
Abb. 2: Nachweis der mRNA-Expression von DP IV (CD26) und APN (CD13) auf SZ95-Zeiien mittels RT-PCR Fig. 2: Detection of the mRNA expression of DP IV (CD26) and APN (CD13) on SZ95 lines using RT-PCR
Konzentration [μM]Concentration [μM]
Abb. 3: Dosisabhängiger Effekt von Inhibitoren der DP IV (Lys[Z(NO2)]- thiazolidid) und der Aminopeptidase N (Actinonin) auf die DNA-Synthese humaner SZ95-Sebozyten.Fig. 3: Dose-dependent effect of DP IV (Lys [Z (NO 2 )] thiazolidide) and aminopeptidase N (actinonin) inhibitors on the DNA synthesis of human SZ95 sebocytes.
Die Zellen wurden über 48 Stunden mit den angegebenen Konzentrationen der Inhibitoren inkubiert. Anschließend wurde dem Kulturmedium 3[H]-Methyl- Thymidin zugesetzt und nach weiteren 6 Stunden die in die DNA eingebaute Menge an 3[H]-Thymidin gemessen. The cells were incubated for 48 hours with the indicated concentrations of the inhibitors. Then 3 [H] methyl thymidine was added to the culture medium and after a further 6 hours the amount of 3 [H] thymidine incorporated into the DNA was measured.

Claims

Patentansprüche claims
I . Verwendung von Inhibitoren der Dipeptidylpeptidase IV (DP IV) sowie von Enzymen mit gleicher Substratspezifität (DP IV-analoge Enzymaktivität) oder/und von Inhibitoren der Alanyl-Aminopeptidase (Aminopeptidase N, APN) bzw. Enzymen gleicher Substratspezifität (APN-analoge Enzymaktivität) zur Herstellung pharmazeutischer Zubereitungen zur Hemmung der Proliferation (DNA-Synthese) humaner Sebozyten.I. Use of inhibitors of dipeptidyl peptidase IV (DP IV) and of enzymes with the same substrate specificity (DP IV-analogous enzyme activity) or / and of inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) or enzymes of the same substrate specificity (APN-analogous enzyme activity) Production of pharmaceutical preparations for inhibiting the proliferation (DNA synthesis) of human sebocytes.
2. Verwendung nach Anspruch 1 , worin die Inhibitoren der DP IV Xaa-Pro-Dipeptide (Xaa = α-Aminosäure bzw. seitenkettengeschütztes Derivat), entsprechende Derivate, vorzugsweise Dipeptidphosphonsäurediarylester, Dipeptidboronsäuren (z.B. Pro-boro-Pro) und deren Salze, Xaa-Xaa-(Trp)-Pro-(Xaa)n-Peptide (Xaa = α-Aminosäure, n = 0 bis10), entsprechende Derivate und deren Salze, Aminosäure (Xaa)-amide, entsprechende Derivate und deren Salze, wobei Xaa eine α- Aminosäure bzw. ein seitenkettengeschütztes Derivat, vorzugsweise Nε-4- Nitrobenzyloxycarbonyl-L-Lysin, L-Isoleucin, L-Valin, L-Tryptophan, L-Prolin ist und als Amidstruktur cyclische Amine, z.B. Pyrrolidin, Piperidin, Thiazolidin und deren Derivate fungieren, Tryptophan-1 ,2,3,4-tetrahydroisochinolin-3-carbonsäu- rederivate (TSL) und/oder (2S,2S',2S")-2-[2'-[2"-amino-3"-(indol-3'"-yl)-1 "- oxoprolyl]-r,2',3',4'-tetrahydro-6'8'-dihydroxy-7-methoxyisochinol-3-yl-carbonyl- amino]-4-hydromethyl-5-hydropentansäure (TMC-2A) sind.2. Use according to claim 1, wherein the inhibitors of the DP IV Xaa-Pro dipeptides (Xaa = α-amino acid or side chain-protected derivative), corresponding derivatives, preferably diaryl dipeptide phosphonate, dipeptide boronic acids (eg Pro-boro-Pro) and their salts, Xaa -Xaa- (Trp) -Pro- (Xaa) n-peptides (Xaa = α-amino acid, n = 0 to 10), corresponding derivatives and their salts, amino acid (Xaa) amides, corresponding derivatives and their salts, where Xaa is a α-amino acid or a side-chain protected derivative, preferably N ε -4-nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline and as an amide structure cyclic amines, for example pyrrolidine, piperidine, thiazolidine and their derivatives function, tryptophan-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives (TSL) and / or (2S, 2S ' , 2S " ) -2- [2 ' - [2 " -amino-3 " - (indol-3 '" -yl) -1 " - oxoprolyl] -r, 2', 3 ' , 4 ' -tetrahydro-6 ' 8'-dihydroxy-7-methoxyisoquinol-3-yl-carbonylamino] -4-methyl-5-hydro hydropentans acid (TMC-2A).
3. Verwendung nach Anspruch 1 , worin Aminosäureamide, z.B. Nε-4-Nitrobenzyl- oxycarbonyl-L-Lysin-thiazolidid, -pyrrolidid und -piperidid sowie das entsprechende 2-Cyanothiazolidid-, 2-Cyanopyrrolidid- und 2-Cyanopiperidid-derivat als DP IV-lnhibitoren eingesetzt werden.3. Use according to claim 1, wherein amino acid amides, for example N ε -4-nitrobenzyloxycarbonyl-L-lysine thiazolidide, pyrrolidide and piperidide, and the corresponding 2-cyanothiazolidide, 2-cyanopyrrolidide and 2-cyanopiperidide derivative as DP IV inhibitors can be used.
4. Verwendung nach Anspruch 1 , wobei als Inhibitoren der APN Actinonin, Leuhi- stin, Phebestin, Amastatin, Bestatin, Probestin, ß-Aminothiole, α-Aminophosphin- säuren, α-Aminophosphinsäurederivate, vorzugsweise D-Phe-YPO(OH)-CH2]- Phe-Phe und deren Salze fungieren. 4. Use according to claim 1, wherein as inhibitors of APN actinonin, leuhistin, phebestin, amastatin, bestatin, probestin, β-aminothiols, α-aminophosphinic acids, α-aminophosphinic acid derivatives, preferably D-Phe-YPO (OH) - CH 2 ] - Phe-Phe and their salts act.
5. Verwendung von Inhibitorkombinationen nach einem der Ansprüche 1 bis 4 zur Herstellung pharmazeutischer Zubereitungen zur Vorbeugung und Therapie von sowohl benignen follikulären Hyperproliferationszuständen (Akne, akneiforme follikuläre Reaktionen, Steatocystoma multiplex, Talgdrüsen-Naevi, senile Talgdrüsenhypertrophie, Seborrhoe der Haut und Haare, SAHA-Syndrom [Seborrhoe, Akne, Hirsutismus, Alopecie]) als auch malignen follikulären Hyperproliferationszuständen (Mischtumoren, Sebaceome, Nävus sebaceus mit maligner Entwicklung, Talgdrüsen-Tumoren, Talgdrüsen-CA).5. Use of inhibitor combinations according to one of claims 1 to 4 for the manufacture of pharmaceutical preparations for the prevention and therapy of both benign follicular hyperproliferation conditions (acne, acneiform follicular reactions, steatocystoma multiplex, sebaceous glandular nevi, senile sebaceous gland hypertrophy, seborrhea of the skin and hair, skin and hair, seborrhea, skin and hair, Syndrome [seborrhea, acne, hirsutism, alopecia]) as well as malignant follicular hyperproliferation conditions (mixed tumors, sebaceomas, sebaceous nevus with malignant development, sebaceous gland tumors, sebaceous gland CA).
6. Verwendung von Inhibitoren der Dipeptidylpeptidase IV (DP IV) sowie von Enzymen mit gleicher Substratspezifität (DP IV-analoge Enzymaktivität) oder/und von Inhibitoren der Alanyl-Aminopeptidase (Aminopeptidase N, APN) bzw. Enzymen gleicher Substratspezifität (APN-analoge Enzymaktivität) zur Hemmung der Proliferation (DNA-Synthese) humaner Sebozyten.6. Use of inhibitors of dipeptidyl peptidase IV (DP IV) and of enzymes with the same substrate specificity (DP IV-analogous enzyme activity) or / and of inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) or enzymes of the same substrate specificity (APN-analogous enzyme activity ) to inhibit the proliferation (DNA synthesis) of human sebocytes.
7. Verwendung nach Anspruch 6, worin die Inhibitoren der DP IV Xaa-Pro-Dipeptide (Xaa = α-Aminosäure bzw. seitenkettengeschütztes Derivat), entsprechende Derivate, vorzugsweise Dipeptidphosphonsäurediarylester, Dipeptidboronsäuren (z.B. Pro-boro-Pro) und deren Salze, Xaa-Xaa-(Trp)-Pro-(Xaa)n-Peptide (Xaa = α-Aminosäure, n = 0-10), entsprechende Derivate und deren Salze, Aminosäure (Xaa)-amide, entsprechende Derivate und deren Salze, wobei Xaa eine α- Aminosäure bzw. ein seitenkettengeschütztes Derivat, vorzugsweise Nε-4- Nitrobenzyloxycarbonyl-L-Lysin, L-Isoleucin, L-Valin, L-Tryptophan, L-Prolin ist und als Amidstruktur cyclische Amine, z.B. Pyrrolidin, Piperidin, Thiazolidin und deren Derivate fungieren, Tryptophan-1 ,2,3,4-tetrahydroisochinolin-3- carbonsäurederivate (TSL) und/oder (2S,2S',2S")-2-[2'-[2"-amino-3"-(indoI-3'"- yl)-1 "-oxoprolyl]-1 ',2',3',4'-tetrahydro-6'8'-dihydroxy-7-methoxyisochinol-3-yl- carbonylamino]-4-hydromethyl-5-hydropentansäure (TMC-2A) sind.7. Use according to claim 6, wherein the inhibitors of the DP IV Xaa-Pro dipeptides (Xaa = α-amino acid or side chain-protected derivative), corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters, dipeptide boronic acids (eg Pro-boro-Pro) and their salts, Xaa -Xaa- (Trp) -Pro- (Xaa) n-peptides (Xaa = α-amino acid, n = 0-10), corresponding derivatives and their salts, amino acid (Xaa) amides, corresponding derivatives and their salts, where Xaa is an α-amino acid or a side-chain-protected derivative, preferably N ε -4-nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline, and the amide structure is cyclic amines, for example pyrrolidine, piperidine, thiazolidine and their derivatives act, tryptophan-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives (TSL) and / or (2S, 2S ' , 2S " ) -2- [2 ' - [2 " -amino-3 " - (indoI-3 ' "- yl) -1" -oxoprolyl] -1 ' , 2 ', 3', 4'-tetrahydro-6'8 ' -dihydroxy-7-methoxyisoquinol-3-yl-carbonylamino] -4 -hydromethyl-5-hydropentanoic acid (TMC -2A).
8. Verwendung nach Anspruch 6, worin Aminosäureamide, z.B. Nε-4- Nitrobenzyloxy-carbonyl-L-Lysin-thiazolidid, -pyrrolidid und -piperidid sowie das entsprechende 2-Cyanothiazolidid-, 2-Cyanopyrrolidid- und 2-Cyanopiperidid- derivat als DP IV-lnhibitoren eingesetzt werden. 8. Use according to claim 6, wherein amino acid amides, for example N ε -4-nitrobenzyloxycarbonyl-L-lysine thiazolidide, pyrrolidide and piperidide, and the corresponding 2-cyanothiazolidide, 2-cyanopyrrolidide and 2-cyanopiperidide derivative as DP IV inhibitors can be used.
9. Verwendung nach Anspruch 6, wobei als Inhibitoren der APN Actinonin, Leuhi- stin, Phebestin, Amastatin, Bestatin, Probestin, ß-Aminothiole, α-Aminophosphin- säuren, α-Aminophosphinsäurederivate, vorzugsweise D-Phe-ΨPO(OH)-CH2]- Phe-Phe und deren Salze fungieren.9. Use according to claim 6, wherein as inhibitors of APN actinonin, leuhistin, phebestin, amastatin, bestatin, probestin, β-aminothiols, α-aminophosphinic acids, α-aminophosphinic acid derivatives, preferably D-Phe-ΨPO (OH) - CH 2 ] - Phe-Phe and their salts act.
10. Verwendung von Inhibitorkombinationen nach einem der Ansprüche 6 bis 9 zur Vorbeugung und Therapie von sowohl benignen follikulären Hyperproliferations- zuständen (Akne, akneiforme follikuläre Reaktionen, Steatocystoma multiplex, Talgdrüsen-Naevi, senile Talgdrüsenhypertrophie, Seborrhoe der Haut und Haare, SAHA-Syndrom [Seborrhoe, Akne, Hirsutismus, Alopecie]) als auch malignen follikulären Hyperproliferationszuständen (Mischtumoren, Sebaceome, Nävus sebaceus mit maligner Entwicklung, Talgdrüsen-Tumoren, Talgdrüsen-CA).10. Use of inhibitor combinations according to one of claims 6 to 9 for the prevention and therapy of both benign follicular hyperproliferation conditions (acne, acneiform follicular reactions, steatocystoma multiplex, sebaceous gland nevi, senile sebaceous gland hypertrophy, seborrhea of the skin and hair [SAHA syndrome Seborrhea, acne, hirsutism, alopecia]) as well as malignant follicular hyperproliferations (mixed tumors, sebaceomas, sebaceous nevus with malignant development, sebaceous gland tumors, sebaceous gland CA).
11. Verfahren zur Hemmung der Proliferation (DNA-Synthese) humaner Sebozyten unter Einschluß der ein- oder mehrmaligen Verabreichung einer phamazeuti- schen Zubereitung an einen Patienten mit entsprechendem Krankheitsbild, umfassend die Verabreichung von Inhibitoren der Dipeptidylpeptidase IV (DP IV) sowie von Enzymen mit gleicher Substratspezifität (DP IV-analoge Enzymaktivität) oder/und von Inhibitoren der Alanyl-Aminopeptidase (Aminopeptidase N, APN) bzw. Enzymen gleicher Substratspezifität (APN-analoge Enzymaktivität).11. A method for inhibiting the proliferation (DNA synthesis) of human sebocytes, including the single or repeated administration of a pharmaceutical preparation to a patient with a corresponding clinical picture, comprising the administration of inhibitors of dipeptidyl peptidase IV (DP IV) and of enzymes same substrate specificity (DP IV-analogous enzyme activity) or / and inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) or enzymes of the same substrate specificity (APN-analogous enzyme activity).
12. Verfahren nach Anspruch 11 , worin die Inhibitoren der DP IV Xaa-Pro-Dipeptide (Xaa = α-Aminosäure bzw. seitenkettengeschütztes Derivat), entsprechende Derivate, vorzugsweise Dipeptidphosphonsäurediarylester, Dipeptidboronsäuren (z.B. Pro-boro-Pro) und deren Salze, Xaa-Xaa-(Trp)-Pro-(Xaa)n-Peptide (Xaa = α-Aminosäure, n = 0-10), entsprechende Derivate und deren Salze, Aminosäure (Xaa)-amide, entsprechende Derivate und deren Salze, wobei Xaa eine α- Aminosäure bzw. ein seitenkettengeschütztes Derivat, vorzugsweise Nε-4- Nitrobenzyloxycarbonyl-L-Lysin, L-Isoleucin, L-Valin, L-Tryptophan, L-Prolin ist und als Amidstruktur cyclische Amine, z.B. Pyrrolidin, Piperidin, Thiazolidin und deren Derivate fungieren, Tryptophan-1 ,2,3,4-tetrahydroisochinolin-3- carbonsäure-derivate (TSL) und/oder (2S,2S',2S")-2-[2'-[2"-amino-3"-(indol- 3"'-yl)-1 "-oxoprolyl]-1 ',2',3',4'-tetrahydro-6'8'-dihydroxy-7-methoxyisochinol-3- yl-carbonyl-amino]-4-hydromethyl-5-hydropentansäure (TMC-2A) sind. 12. The method according to claim 11, wherein the inhibitors of the DP IV Xaa-Pro dipeptides (Xaa = α-amino acid or side chain-protected derivative), corresponding derivatives, preferably dipeptide phosphonate diaryl esters, dipeptide boronic acids (eg Pro-boro-Pro) and their salts, Xaa -Xaa- (Trp) -Pro- (Xaa) n-peptides (Xaa = α-amino acid, n = 0-10), corresponding derivatives and their salts, amino acid (Xaa) amides, corresponding derivatives and their salts, where Xaa is an α-amino acid or a side-chain-protected derivative, preferably N ε -4-nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline, and the amide structure is cyclic amines, for example pyrrolidine, piperidine, thiazolidine and their derivatives act, tryptophan-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives (TSL) and / or (2S, 2S ' , 2S " ) -2- [2 ' - [2" -amino- 3 " - (indole- 3"'- yl) -1 "-oxoprolyl] -1', 2 ', 3', 4'-tetrahydro-6 ' 8 ' -dihydroxy-7-methoxyisoquinol-3-yl-carbonyl- amino] -4-hydromethyl-5-hydropentanoic acid ( TMC-2A).
13. Verfahren nach Anspruch 11 , worin Aminosäureamide, z.B. Nε-4-Nitrobenzyloxy- carbonyl-L-Lysin-thiazolidid, -pyrrolidid und -piperidid sowie das entsprechende 2- Cyanothiazolidid-, 2-Cyanopyrrolidid- und 2-Cyanopiperidid-derivat als DP IV- Inhibitoren eingesetzt werden.13. The method according to claim 11, wherein amino acid amides, for example N ε -4-nitrobenzyloxycarbonyl-L-lysine thiazolidide, pyrrolidide and piperidide and the corresponding 2-cyanothiazolidide, 2-cyanopyrrolidide and 2-cyanopiperidide derivative as DP IV inhibitors are used.
14. Verfahren nach Anspruch 11 , wobei als Inhibitoren der APN Actinonin, Leuhistin, Phebestin, Amastatin, Bestatin, Probestin, ß-Aminothiole, α-Aminophosphinsäu- ren, α-Aminophosphinsäurederivate, vorzugsweise D-Phe-YPO(OH)-CH2]-Phe- Phe und deren Salze fungieren.14. The method according to claim 11, wherein as APN inhibitors actinonin, leuhistine, phebestin, amastatin, bestatin, probestin, β-aminothiols, α-aminophosphinic acids, α-aminophosphinic acid derivatives, preferably D-Phe-YPO (OH) -CH 2 ] -Phe- Phe and their salts act.
15. Verfahren nach einem der Ansprüche 11 bis 14 zur Vorbeugung und Therapie von sowohl benignen follikulären Hyperproliferationszuständen (Akne, akneiforme follikuläre Reaktionen, Steatocystoma multiplex, Talgdrüsen-Naevi, senile Talgdrüsenhypertrophie, Seborrhoe der Haut und Haare, SAHA-Syndrom [Seborrhoe, Akne, Hirsutismus, Alopecie]) als auch malignen follikulären Hyperproliferationszuständen (Mischtumoren, Sebaceome, Nävus sebaceus mit maligner Entwicklung, Talgdrüsen-Tumoren, Talgdrüsen-CA) bei Patienten unter Einschluß der einmaligen oder mehrmaligen Verabreichung einer pharmazeutischen Zubereitung mit einem oder mehreren Inhibitoren der DP IV und/oder APN.15. The method according to any one of claims 11 to 14 for the prevention and therapy of both benign follicular hyperproliferation conditions (acne, acneiform follicular reactions, steatocystoma multiplex, sebaceous gland nevi, senile sebaceous gland hypertrophy, seborrhea of the skin and hair, SAHA syndrome [seborrhea, acne Hirsutism, alopecia]) as well as malignant follicular hyperproliferation conditions (mixed tumors, sebaceomas, sebaceous nevus with malignant development, sebaceous gland tumors, sebaceous gland CA) in patients, including the single or repeated administration of a pharmaceutical preparation with one or more inhibitors of DP IV and / or APN.
16. Pharmazeutische Zubereitungen, umfassend Inhibitoren der Dipeptidylpeptidase IV (DP IV) oder DP IV-analoger Enzymaktivität oder/und Inhibitoren der Alanyl- Aminopeptidase (Aminopeptidase N, APN) bzw. Enzyme gleicher Substratspezifität (APN-analoge Enzymaktivität und in Kombination mit an sich bekannten Träger-, Zusatz- und/oder Hilfsstoffen.16. Pharmaceutical preparations comprising inhibitors of dipeptidyl peptidase IV (DP IV) or DP IV-analogous enzyme activity or / and inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) or enzymes of the same substrate specificity (APN-analogous enzyme activity and in combination with themselves known carriers, additives and / or auxiliaries.
17. Pharmazeutische Zubereitung nach Anspruch 16, umfassend als Inhibitoren der DP IV Xaa-Pro-Dipeptide (Xaa = α-Aminosäure bzw. seitenketten-geschützte Derivate), entsprechende Derivate, vorzugsweise Dipeptidphosphon- säurediarylester und deren Salze, Xaa-Xaa-(Trp)-Pro-(Xaa)n-Peptide (Xaa = α- Aminosäuren, n=0-10), entsprechende Derivate und deren Salze bzw. Aminosäure (Xaa)-amide, entsprechende Derivate und deren Salze, wobei Xaa eine α- Aminosäure bzw. seitenkettengeschütztes Derivat, vorzugsweise Nε-4- Nitrobenzyloxycarbonyl-L-Lysin, L-Isoleucin, L-Valin, L-Tryptophan, L-Prolin ist und als Amidstruktur cyclische Amine, z.B. Pyrrolidin, Piperidin, Thiazolidin und deren Derivate fungieren, Tryptophan-1 ,2,3,4-tetrahydroisochinolin-3-carbonsäu- re-derivate (TSL) und/oder (2S,2S',2S")-2-[2'-[2"-amino-3"-(indol-3'"-yl)-1 "- oxoprolyl]-1 ',2',3',4'-tetrahydro-6'8'-dihydroxy-7-methoxyisochinol-3-yl-carbonyl- amino]-4-hydromethyl-5-hydropentansäure (TMC-2A).17. Pharmaceutical preparation according to claim 16, comprising as inhibitors of the DP IV Xaa-Pro dipeptides (Xaa = α-amino acid or side chain-protected derivatives), corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters and their salts, Xaa-Xaa- (Trp ) -Pro- (Xaa) n-peptides (Xaa = α-amino acids, n = 0-10), corresponding derivatives and their salts or amino acid (Xaa) -amides, corresponding derivatives and their salts, where Xaa is an α-amino acid or side chain protected derivative, preferably N ε -4- Nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline and cyclic amines such as pyrrolidine, piperidine, thiazolidine and their derivatives act as amide structure, tryptophan-1, 2,3,4-tetrahydroisoquinoline -3-carboxylic acid derivatives (TSL) and / or (2S, 2S ' , 2S ") - 2- [2 ' - [2" -amino-3 " - (indol-3 '" -yl) -1 "- oxoprolyl] -1 ', 2', 3 ', 4'-tetrahydro-6' 8 '-dihydroxy-7-methoxyisochinol-3-yl-carbonyl amino] -4-methyl-5-hydro hydro pentanoic acid (TMC-2A ).
18. Pharmazeutische Zubereitung nach Anspruch 16, umfassend als Inhibitoren der DP IV Aminosäureamide, z.B. Nε-4-Nitrobenzyloxy-carbonyl-L-Lysin-thiazolidid, -pyrrolidid und -piperidid sowie das entsprechende 2-Cyanothiazolidid-, 2-Cyano- pyrrolidid- und 2-Cyanopiperididderivat.18. Pharmaceutical preparation according to claim 16, comprising as inhibitors of DP IV amino acid amides, for example N ε -4-nitrobenzyloxycarbonyl-L-lysine thiazolidide, pyrrolidide and piperidide, and the corresponding 2-cyanothiazolidide, 2-cyano-pyrrolidide - and 2-cyanopiperidide derivative.
19. Pharmazeutische Zubereitung nach Anspruch 16 umfassend als Inhibitoren der APN Actinoin, Leuhistin, Phebestin, Amastin, Bestatin, Probestin, ß-Aminothiole, a-Aminophosphinsäuren, a-Aminophosphinsäurederivate, bevorzugt D-Phe- ψ[PO(OH)-CH2]-Phe-Phe und deren Salze.19. Pharmaceutical preparation according to claim 16 comprising as inhibitors of APN actinoin, leuhistine, phebestin, amastine, bestatin, probestin, ß-aminothiols, a-aminophosphinic acids, a-aminophosphinic acid derivatives, preferably D-Phe- ψ [PO (OH) -CH 2 ] -Phe-Phe and their salts.
20. Pharmazeutische Zubereitung nach einem der Ansprüche 16 bis 19, umfassend zwei oder mehrere der Inhibitoren der DP IV bzw. DP IV-analoger Enzymaktivität oder/und der APN bzw. APN-analoger Enzymaktivität in räumlich getrennter Formulierung in Kombination mit an sich bekannten Träger-, Hilfs- und/oder Zusatzstoffen zur gleichzeitigen oder zeitlich unmittelbar aufeinanderfolgenden Verabreichung mit dem Ziel einer gemeinsamen Wirkung.20. Pharmaceutical preparation according to one of claims 16 to 19, comprising two or more of the inhibitors of DP IV or DP IV-analogous enzyme activity or / and the APN or APN-analogous enzyme activity in spatially separate formulation in combination with known carriers -, auxiliaries and / or additives for simultaneous or immediately sequential administration with the aim of a common effect.
21. Pharmazeutische Zubereitung gemäß Ansprüche 16 bis 20 für die systemische Anwendung zur oralen, transdermalen, intravenösen, subcutanen, intracutanen, intramuskulären, rektalen, vaginalen, sublingualen Applikation zusammen mit an sich bekannten Träger-, Hilfs- und/oder Zusatzstoffen.21. Pharmaceutical preparation according to claims 16 to 20 for systemic use for oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application together with known carriers, auxiliaries and / or additives.
22. Pharmazeutische Zubereitung gemäß Ansprüchen 16 bis 20 für die topische Anwendung in Form von z.B. Cremes, Salben, Pasten, Gelen, Lösungen, Sprays, Lipo- bzw. Nanosomen, Schüttelmixturen, Hydrokolloidverbänden bzw. anderen dermatologischen Grundlagen/ Vehikeln, einschließlich instillativer Applikation. 22. Pharmaceutical preparation according to claims 16 to 20 for topical use in the form of e.g. Creams, ointments, pastes, gels, solutions, sprays, liposomes or nanosomes, shake mixtures, hydrocolloid dressings or other dermatological bases / vehicles, including instillative application.
EP03709761A 2002-03-15 2003-03-07 Pharmaceutical preparations of inhibitors of aminopeptidase n alone or in combination with inhibitors of dipeptidylpeptidase iv for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states Expired - Lifetime EP1487475B1 (en)

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DE10211555 2002-03-15
DE10211555A DE10211555A1 (en) 2002-03-15 2002-03-15 Use of the inhibitors of enzymes with activities of the aminopeptidase N and / or the dipeptidyl peptidase IV and pharmaceutical preparations thereof for the therapy and prevention of dermatological diseases with sebocytic hyperproliferation and changed differentiation states
PCT/EP2003/002356 WO2003077935A1 (en) 2002-03-15 2003-03-07 Use of enzyme inhibitors with aminopeptidase n and/or dipeptidylpeptidase iv activities and pharmaceutical preparations produced therefrom for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states

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EA200401212A1 (en) 2005-02-24
EP1487475B1 (en) 2010-09-29
JP4424994B2 (en) 2010-03-03
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DK1487475T3 (en) 2011-01-24
JP2005520825A (en) 2005-07-14
US7683034B2 (en) 2010-03-23
CN1738636B (en) 2012-07-18
EA008745B1 (en) 2007-08-31
AU2003214105A2 (en) 2003-09-29
WO2003077935A1 (en) 2003-09-25
ATE482715T1 (en) 2010-10-15
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